1.1 Field of the Invention
The invention concerns apparatus and methods for treating amblyopic conditions and is particularly directed to methods that correct this visual deficiency in adults.
1.2 Description of Related Art
Amblyopia, Greek for xe2x80x9cblunt visionxe2x80x9d, is the failure of an anatomically intact eye to develop normal visual acuity. Amblyopia affects five to seven million individuals in the United States alone, with an estimated 70,000 new cases annually. Amblyopia accounts for more visual loss in the under-45 age group than all other ocular diseases, including trauma. In the lay press, this condition is often referred to as xe2x80x9clazy eyexe2x80x9d. The term lazy eye is to be avoided, however, as it may also be used in the lay press to describe strabismus (xe2x80x9ccrossedxe2x80x9d eye) as well. While a crossed eye may become amblyopic (strabismic amblyopia), not all crossed eyes are amblyopic nor are all amblyopic eyes crossed.
Amblyopia represents a failure of the affected eye to develop normal synaptic connections with the visual cortex (Sireteanu, 1982). This is thought to result from an abnormal outcome of the competitive process of visual development. During visual development, the roughly 1.2 million nerve fibers that make up the optic nerve of each eye compete for synaptic connections in the brain (Cynader 1982). Under normal developmental circumstances, the visual input from each eye is roughly equal to that of its counterpart therefore each eye is assigned a proportionately equal number of synapses in the visual processing areas of the brain and allowed to realize its full visual potential. In humans, this process is thought to begin at birth and continues until roughly 8 years of age.
The number of synapses available within a given area of cortex is limited and once this number of synapses is reached, the development of additional synapses cannot occur without the loss or destruction of other synapses in the same cortical area. This phenomenon is known as the conservation of total axonal arborizations (Sabel 1988). In amblyopia, one eye is disadvantaged relative to the contralateral eye. This may be due to the need for spectacle correction in one eye more so than the other (refractive amblyopia), by the presence of a crossed eye (strabismic amblyopia) or by the presence of an obstruction in the visual axis of one eye (cataract, ptosis of the upper eyelid, or presence of an eyelid mass, for example). During visual development, the better-seeing eye is therefore assigned a greater proportion of the available synapses in visual cortex than its poorer seeing counterpart. In this way, the better-seeing eye may control more synapses in the cortex than it needs for optimal vision. With a limited number of synapses available in visual cortex, the poorer-seeing eye is left with fewer synapses than it needs for normal vision. If this situation remains uncorrected beyond the critical period of visual development, these synaptic connections become fixed, and neither correction of the weaker eye""s underlying disadvantage nor the patching therapy described below will return the eye to normal visual acuity. If this situation is recognized during the first years of life (before) the critical period of visual development is complete however, treatment is often possible.
The problem is typically addressed in the following manner: First, the underlying condition that initially disadvantaged the weaker eye (i.e., the need for glasses, obstruction by a ptotic eyelid, strabismus, etc) is corrected. Second, the better-seeing eye is temporarily disadvantaged relative to the amblyopic eye. This is usually accomplished via occlusion of the dominant eye with an eye patch or similar occlusive device. In lieu of a patch, it is also possible to use cycloplegic eye drops such as atropine in the dominant eye to cause visual blurring. This practice is sometimes referred to as xe2x80x9cpharmacologic patchingxe2x80x9d. In this way, the amblyopic eye is given an opportunity to form sufficient synaptic connections to allow useful vision before the critical period is complete and synaptic connections become fixed.
If occlusion therapy is used too aggressively, however, it is possible to make the previously dominant eye amblyopic. For this reason, regular visual acuity checks are necessary throughout amblyopia therapy. As a general rule, visual acuity is checked in both eyes on a schedule of 1 week per year of patient life. For example, a 1-year old undergoing full-time occlusion therapy would have his or her vision evaluated weekly; a 4-year old undergoing full-time occlusion therapy would have his or her vision evaluated every four weeks. These checkups include an examination to ensure that the underlying cause of the amblyopia (e.g., refractive error, ptotic eyelid, strabismus, etc) is being managed appropriately, as well as an assessment of visual acuity in each eye. In older literate children, this is done with a standard eye chart. In younger children who are verbal but not yet literate, standardized picture charts are used to determine visual acuity. In preverbal children, the task is significantly more difficult and often involves the examiner observing the child""s ability to fixate upon and follow a small target with each eye.
Thus the two mainstays of amblyopia management in children are the prevention of any condition that could disadvantage the vision of one eye relative to its counterpart, and occlusive therapy, whether by physical patching or pharmacologic cycloplegia. Occlusive therapy is problematic for several reasons: First, the technique is only effective during the so-called critical period during which the visual system is developing. In humans, this period begins at birth and is largely complete by eight years of age, although this limit is subject to debate. The older the patient is, the less successful occlusive therapy tends to be, with occlusive therapy in adults having little or no significant value.
Second, and of significant importance, keeping an occlusive dressing over the dominant eye of a young child is a challenge for child, parent, and physician alike. Understandably, many children fail occlusive therapy due to noncompliance. This leaves these patients with permanent visual loss in the amblyopic eye, as occlusion therapy is not efficacious in adults and there are currently no effective methods for the treatment of adult amblyopia.
1.3 Deficiencies in the Prior Art
The challenge in an amblyopic patient therefore is to improve vision in the amblyopic eye without causing significant reduction of visual acuity in the dominant eye. There is currently no such therapy available to adult patients or to pediatric patients refractory to occlusion therapy. The lack of a demonstrably effective treatment for adult amblyopia leaves many patients with severely limited, often debilitating, vision. The prevalence of adult amblyopia indicates the need to develop a therapy to improve vision in an amblyopic eye. This is of paramount importance in patients who have sustained vision loss in their dominant non-amblyopic eye from disease or trauma. Significant alleviation of the handicap caused by visual deprivation arising from this condition would allow this population of adults to function more effectively in society and to enjoy a better quality of life.
The invention addresses the need for providing a treatment for improving vision in an amblyopic eye. The method utilizes selected drugs to induce a sustained yet reversible interruption of optic nerve transmission in the dominant eye, which is sufficient to allow complete or significant visual recovery in the amblyopic eye. The disclosed procedures are particularly suitable for treatment in adults for whom conventional methods used in children are ineffective.
Accordingly, the invention in one aspect is a method of safely interfering with impulse transmission from the dominant eye to the brain. This is accomplished with a drug that effectively blocks nerve transmission. Many drugs are known to interfere with nerve conduction, including for example, local anesthetics such as lidocaine and bupivicaine; cocaine; bufotoxins; picrotoxin; botulinum toxin; tetrodotoxin; snake venom toxins such as bungarotoxin; dinoflagellate toxins such as those produced by Pfiesteria pisicida; electric stimulation; gamma-aminobutyric acid; norepinephrine; levodopa/carbidopa; benzodiazepines; and 4-aminopyridine.
Selection of appropriate drugs may be determined in animal models to assess safety and efficacy. Preferred drugs recognized as effective in blocking nerve transmission are lidocaine and bupivicaine. These agents are considered by one skilled in the art as drugs of choice for reasons of safety and long term history of use. In particular, the safety of these agents in the orbit socket of the human eye is well established. These drugs are routinely used for retrobulbar and peribulbar anesthesia of the eye in a variety of ophthalmic procedures including cataract surgery, glaucoma surgery, and retinovitreal surgery. Preservative-free 1% lidocaine HCL is also routinely used within the eye as an adjunct to topical anesthetics during cataract surgery.
The safety of 1% preservative-free lidocaine in the anterior segment of the eye is well established as the drug is frequently used as an anesthetic adjunct to topical anesthesia in modern cataract surgery. Anecdotal reports of 1% preservative-free lidocaine entering the posterior segment of the eye (Hoffman and Fine, 1997) have demonstrated that the drug blocked transmission of visual signals to the patient""s brain as the patient rapidly developed xe2x80x9cno light perceptionxe2x80x9d vision. This effect was reversible, however, and vision returned in the eye within hours of discontinuing the drug. The authors report no evidence of retinal toxicity following the exposure to 1% preservative-free lidocaine.
Another aspect of the invention is a method of providing controlled amounts of the selected drug to the targeted nerve. In one embodiment, a device employing a small drug delivery pump directs an appropriate drug through a canula into the orbit (socket) of the dominant eye. A fenestrated canula or catheter, preferably made of flexible, biocompatible material, is placed into the orbit of the dominant eye using one of several maneuvers. The catheter can be inserted without guidance into the orbit over a needle. A similar xe2x80x9cblind stickxe2x80x9d technique is used to induce peribulbar or retrobulbar anesthesia prior to ocular surgery. The needle is then withdrawn, leaving the catheter in the orbit. The catheter can also be advanced into the orbit under CT (computerized tomography) or fluoroscopic guidance. Finally, guidance of the catheter into the orbit may be facilitated by electronic feedback. The infusion catheter or canula can include a conductive strip allowing the catheter to function as a sensing electrode. Alternatively, the infusion catheter can be introduced over a needle possessing an insulated shaft and a conductive tip such that the needle acts as a sensing electrode. In either case, photic stimulation is provided to the dominant eye thereby producing impulses in its optic nerve which are detected by the electrode as it comes in closer and closer proximity to the optic nerve. In this way, feedback from the electrode allows the surgeon to accurately place the catheter near the optic nerve while feedback from the electrode allows the surgeon to avoid traumatizing the optic nerve with the needle or catheter.
The catheter may also be placed in close proximity to the optic nerve by direct visualization using a surgical approach such as a medial orbitotomy. While more invasive, this method would allow exact placement of the canula near the optic nerve. Using this technique, placement of the canula could be accompanied by optic nerve sheath fenestration, a technique in which a xe2x80x9cwindowxe2x80x9d is made into the dural covering of the optic nerve, thereby allowing any infused drugs easier access to the optic nerve.
Following catheter placement, a drug delivery pump supplies an infusion of drug sufficient to decrease or suspend impulse transmission by the optic nerve. The pump is easily miniaturized so that it can be comfortably placed on the neck or behind the ear of the patient or even implanted beneath the conjunctiva with little discomfort or inconvenience. Control of drug delivery can be by manual set in the physician""s office, or adjusted automatically through use of a microprocessor. The microprocessor can be adapted to detect signals from the dominant eye to the optic nerve so that an amount of drug can be administered that is effective to prevent or inhibit the transmission of impulses from the dominant eye to the brain via the optic nerve.
In another embodiment, an appropriately sized canula (similar to the trans-pars plana infusion canula currently used in retinal-vitreous surgery or the trans-pars plana shunt tube used in glaucoma surgery for example) is fixated to the eye using standard surgical techniques. This canula is then connected to a small drug delivery pump, which can be sutured to the sclera and implanted beneath the conjunctiva in the same fashion as the plate of a glaucoma shunt device. The pump then delivers a nerve-blocking agent intraocularly via the canula, thereby interrupting transmission of nerve impulses from the dominant eye to the brain. The pump can deliver a nerve-blocking drug at a fixed, preset rate or may be controlled by any of a number of means including but not limited to radio frequency, optical sensor, inductive control, or manual manipulation across the conjunctiva. The drug delivery pump and canula remain safely implanted beneath the conjunctiva until treatment is complete, after which time the pump and canula can be removed.
In another embodiment, a nerve-blocking agent is delivered intraocularly via an intraocular drug delivery system. This may be accomplished by a variety of methods including but not limited to: time-release inserts, osmotic pumps, conventional electromechanical pumps, or pumps which make use of Micro Electro Mechanical Systems (MEMS) microtechnology.
In yet another embodiment a drug delivery device is implanted within the orbit to administer an appropriate drug to the optic nerve of the dominant eye. A variety of drug delivery devices could be implanted within the orbit including but not limited to: time-release preparations of the drug of choice (pellets of drug combined with a biodegradable matrix, for example), osmotic drug delivery pumps, miniaturized conventional drug delivery pump and pumps which make use of Micro Electro Mechanical Systems (MEMS) technology.
Finally, when electricity is the drug chosen to modulate optic nerve function, a biocompatible electrode, preferably flexible in construction, is placed in the orbit in proximity to the optic nerve instead of a drug delivery catheter. Placement of the electrode may be guided by the methods described above for catheter placement. In lieu of a drug delivery pump, an electrical stimulator circuit is connected to the electrode and used to deliver a current sufficient to interrupt optic nerve transmission.
The disclosed method is a method of treating amblyopia by administering a denervating drug to a dominant eye, monitoring visual acuity in the amblyopic eye, and reversing denervation upon achieving a selected degree of visual acuity in a corresponding amblyopic eye.